Alcoholism is a complex multi-factorial disease with a strong genetic component. The etiology of this disease is due in part to genetic differences in responses to stressors and to variation in the efficacy of ethanol in stress reduction. The molecular basis of this interaction will be studied, leading to a direct evaluation of the hypothesis that mechanisms of stress mediation by alcohol share common molecular pathways with stressors. It will be possible to determine the degree to which shared and separate mechanisms are employed. The project exploits a recently developed microarray technology called transcriptome-QTL mapping to identify the sources of variation in gene expression in the mouse hippocampus. This method enables global mapping of factors controlling the transcriptional response to stress and its modification by alcohol. A large panel of Long Sleep by Short Sleep (LXS) recombinant inbred (RI) strains of mice with sufficient power for the study of traits with small effect or low heritability will be used to map the regulatory loci revolved m mediating the infraction between ethanol and stress. Stressed and unstressed animals will be treated with ethanol or left untreated. Behavioral and physiological stress phenotypes will be measured and mapped in all RI strains. Using oligonucleotide arrays, all strains of the RI panel will be assessed for stress and ethanol related gene expression differences. In the final stage of this work, the identification of the genetic basis of expression differences will be carried out using the novel, large-scale transcriptional analysis to identify major regulatory elements and gene networks that influence the molecular, physiological and behavioral manifestations of alcohol and stress response. This project will generate publicly available transcriptome regulation resources for the alcohol and neuroscience research communities. Because this project focuses on naturally occurring genetic variation in the mouse, the results are likely to extend to human populations with differences in the stress-alcohol interaction.